Vigil for a Doomed Virus

In December 1993 the smallpox virus, one of the worst killers the earth has known, will be put to death by human hands.

Somewhere in Atlanta--for security reasons the jailers won’t disclose the exact location--a condemned killer is waiting to die. This is no ordinary murderer. In its heyday it was responsible not for a few deaths, or even for dozens, but for millions. Nor does this prisoner languish in a common cell. It sits bathed in vapors of liquid nitrogen in a padlocked freezer bolted inside a closet-size room. And though doomed, it feels neither regret for its crimes nor fear for its impending fate. This killer is variola, the virus that causes smallpox, one of history’s greatest and most feared destroyers. Now it awaits its demise at the Centers for Disease Control (CDC).

As a naturally occurring disease, smallpox ceased to be a threat in the world at large about a decade ago, thanks to an intense vaccination campaign. On December 9, 1979, a World Health Organization panel convened in Geneva to ceremoniously sign a parchment emblazoned with a red wax seal. The proclamation, in five languages, read: We, the members of the global commission for the certification of smallpox eradication, certify that smallpox has been eradicated from the world.

With that, you might have thought, smallpox was history. But as it turned out, our very victory over the disease raised some new, quite unprecedented questions. The battle was won, but like prisoners of war, remnants of the viral army remained, held in various laboratories scattered throughout the world. Most researchers had ceased experimenting with these variola stocks. Yet the viruses were still lethal, and with smallpox no longer viewed as a threat, fewer and fewer people were getting vaccinated against it. What if the captive viruses escaped accidentally or were released as a biological weapon?

The specter of that possibility convinced smallpox experts that ridding the world of the awful disease was not enough; variola itself, the agent of the disease, had to go. In December 1990 they decided that all remaining variola viruses should be destroyed--for the first time in history humans have deliberately set out to cause another species’ extinction.

Most public health officials are quietly applauding the prospect. Yet the finality of the decision has also made some researchers nervous. There was a feeling among some scientists, says Giorgio Torrigiani, director of the World Health Organization’s Division of Communicable Diseases, that you shouldn’t irrevocably destroy any life-form, because there might still be things you could learn from it.

Moreover, ordaining an extinction--even the extinction of a virus as nasty as this one--has turned out to be a complicated task. In fact, says Walter Dowdle, deputy director of the CDC, we’ve kept the virus alive this long largely in an effort to come up with a workable plan for destroying it. If all goes according to plan, however, the captive virus will be formally executed by the end of December 1993. And when it is, a unique and dramatic chapter in the history of medicine will finally come to a close.

Smallpox is among mankind’s oldest known infectious enemies. Descriptions of the illness in India date back as far as 1000 b.c.; by the Middle Ages it was a well-documented scourge in Europe, speeding fiercely through susceptible populations. The disease was introduced to the Americas shortly after Columbus landed, and it had killed upwards of 200,000 Incas by the time Pizarro conquered their empire in 1533. During the late 1700s, some 400,000 people were dying of it every year in Europe; in London it was causing almost one out of every ten recorded deaths. And that conveys only a small part of the suffering smallpox inflicted, since it attacked far more people than it ever killed.

Although the disease was horrible, its onset could be deceptively ordinary. About two weeks after you were infected--usually by inhaling the virus on airborne droplets--you developed a fever and splitting headache, often accompanied by backache, chills, and vomiting. Two or three days later, just as these symptoms began to fade, the first signs of the dreaded rash arrived, usually starting with lesions on the tongue and palate. Red spots next appeared on the forehead or the face and spread rapidly to the limbs and trunk. The spots filled with fluid, growing and hardening until they could be manipulated, as though they were small balls of lead embedded in the skin. The result was painfully disfiguring, with swollen pustules sometimes so severe and widespread that they forced the victim’s eyelids shut. At this point, 10 to 16 days after the first symptoms, death from overwhelming infection was most likely to occur. If you survived, the rash gradually improved, scabbing over and eventually healing--though it often branded you with pockmarks for life.

In ancient Asia and Africa there were smallpox gods and goddesses you could pray to for protection; in France you could appeal to Saint Nicaise, a bishop of Rheims who recovered from the pox (only to be promptly killed by the Huns in 452). Tradition also held that smallpox victims could be helped by the color red, a belief that resulted in some of the most curious treatments in the annals of medicine. Sufferers were dressed in red, bathed in red light, plied with red food and drink. These peculiarly medieval treatments persisted even in reputable hospitals until the 1930s, although there’s no evidence whatever that they did the slightest bit of good.

Genuine smallpox intervention has a long history, too. By the thirteenth century the Egyptians had learned that if you rubbed fluid from a smallpox pustule into a scratch on an uninfected person’s arm, he or she would generally develop a mild, nondisfiguring case of the disease and thereafter be immune. (Receiving the virus through the skin produces a much more benign reaction than breathing it in.) The practice of inoculation spread into Turkey, where Lady Mary Wortley Montague, the wife of the English ambassador to Constantinople, learned of it in the early 1700s; she introduced it to England by having her four-year-old daughter successfully inoculated in London in 1721.

The technique, however, had its dangers. You had to stay in quarantine while your mild, induced smallpox ran its course, because you could easily spread the full-blown disease by breathing the virus on others. And there was always a risk of acquiring a severe or even fatal case from your inoculation if the strain pricked into your skin was especially virulent.

It fell to Edward Jenner, a Gloucestershire physician working in the 1790s, to discover--while trying to inoculate his local patients--that some of them were already immune. These patients, he later wrote, had undergone a disease they called the Cow Pox, contracted by milking Cows affected with a peculiar eruption on their teats. On inquiry, it appeared that it had been known among the dairies from time immemorial, and that a vague opinion prevailed that it was a preventive of the Small Pox.

By painstaking experiment Jenner proved that bit of folk wisdom true. Inoculation with the cowpox virus, a close cousin of variola, conferred immunity against smallpox without risk of disease or the need for quarantine. The first true vaccine, the forerunner to today’s vaccinia virus, was born.

With that the fight against smallpox began in earnest. New cases and mortality decreased throughout the 1800s and into the twentieth century. As a result of systematic vaccination, smallpox vanished from England by 1940, from the United States by 1950, from China by 1960. Finally in the mid-1960s the World Health Organization (WHO) launched its ambitious plan to rid the planet of smallpox entirely, with Donald Henderson, now an associate director at the White House Science Office, at the helm.

The WHO strategy was simple: track down all new cases and quickly vaccinate all their contacts. Fortunately, full-fledged smallpox, like rabies, can be prevented from developing even if you’re vaccinated after exposure. And research showed that generally one person infected only two to five others, a manageable rate of spread. Yet many doubted that the scheme would work.

The Third World countries were enthusiastic, says Henderson, recalling the early days of the project. But among the industrial ones there was a widespread feeling that eradication was impossible. A malaria eradication program had been launched earlier with great fanfare, but it ran into trouble because it involved a mosquito vector--it stalled when drug and insecticide resistance emerged. People felt bilked, and they were skeptical of a similar smallpox effort.

One result of their pessimism was that the project was chronically underfunded. Even in 1975, when we were only two years away from total eradication, we were still struggling for money, says Henderson. To compound the problem, the countries where smallpox was making its last stand--Bangladesh, Somalia, Ethiopia--were politically volatile. In fact, Henderson recalls, everything we feared might happen, did. There was a presidential assassination in Bangladesh, and Somalia invaded the Ethiopian lowlands.

After the United Nations declared Ethiopia a dangerous posting, the smallpox teams found themselves the only foreigners working in the war- torn countryside. Traveling by helicopter, by mule, and on foot, the teams combed the backcountry to locate new cases among scattered nomadic groups and vaccinate their contacts.

We’d managed to get the disease out of the Ethiopian highlands, Henderson says, but it was maddeningly persistent among the nomads in the desert. The numbers of cases weren’t large, but there were enough to keep the disease going.

In the turbulence of war some smallpox workers disappeared. One of their helicopters was seized by a band of Somali rebels and held for ransom. The pilot was a Canadian who’d become an enthusiastic vaccinator, remembers Henderson. By the time we negotiated his release, he’d immunized all the rebels. In the last few years of the program the tension level was almost unbearable. We didn’t take many holidays. We knew if we put something off for a week, that might be the week civil war broke out in Bangladesh or Ethiopia or Somalia and the project would suffer another setback.

But their dogged dedication paid off. The last known case occurred in Somalia on October 26, 1977, when Ali Maow Maalin, a 23-year- old hospital cook in the coastal town of Merca, broke out in a poxy rash. He’d apparently caught the disease from two stricken nomads who stopped at the hospital to ask directions: Maalin rode along with them a few hundred feet to the smallpox office; he fell ill ten days later. Fortunately his case was mild and he recovered rapidly.

Four weeks without a case, Henderson remembers, then six weeks, then eight; then several months. After that we had to document that there were no further new cases. That meant two years of an intensive worldwide search, punctuated by rumors of all sorts of outbreaks.

A National Geographic reporter, for example, discovered a tribe in the Amazon that hadn’t been contacted for 30 years. He thought he’d found a smallpox case among them and took a photo, recalls Henderson. Typically, it turned out to be chicken pox (with which mild smallpox can be confused). By 1979 the majority of skeptics were convinced that the virus could no longer be found in nature, and smallpox was officially declared a thing of the past.

If there were any smallpox reservoirs left in the world, we’d have heard about them by now, says Walter Dowdle of the CDC. The disease would spread rapidly because few people now are vaccinated. With today’s rapid communications we’d soon know, even if an outbreak occurred in a remote community in a developing country.

In fact, when smallpox did make one chilling last stand in 1978, its source wasn’t a hidden reservoir in nature but in a laboratory. Janet Parker, a medical photographer in the anatomy department at the University of Birmingham Medical School in Britain developed a fever on August 11 and a rash on August 15. By August 25 the rash had acquired the telltale characteristics of smallpox. By September 11 Parker was dead. Eventually her case was traced back to a smallpox laboratory in the same building as her studio and darkroom. To this day nobody knows for sure exactly how she caught it. But investigators strongly suspect the virus escaped into the air from the lab where it was kept, then drifted through a ventilation system into Parker’s darkroom on the floor above.

Parker’s father suffered a fatal heart attack after visiting her bedside. Then her 70-year-old mother came down with a mild case of smallpox. (She later recovered.) Eight days after Janet Parker’s diagnosis was confirmed, Henry Bedson--a prominent authority on smallpox who headed the lab from which the virus apparently escaped--committed suicide while in quarantine at home. The outbreak spread no further, but Janet Parker’s fatal illness and its tragic consequences led to a wave of panicky coverage in the press. Was smallpox really defunct, or was it simply lying in wait, ready to pounce upon an unsuspecting world as soon as defenses were let down?

It was the Birmingham escape that finally galvanized opinion among world public health authorities: the real danger from variola no longer lay in nature but among the remaining stocks of virus in laboratories.

Which brings us back to that locked freezer in Atlanta. Throughout the late 1970s and early 1980s the World Health Organization encouraged labs still harboring the virus either to destroy their stocks or to ship them for safekeeping to two WHO-designated repositories: the CDC in Atlanta and the Research Institute of Viral Preparations in Moscow. (The choice of locales seems to have been a relic of cold-war realpolitik. The United States and the erstwhile Soviet Union were among the last countries to vaccinate their armies in case smallpox was used for biological warfare.)

Japan shipped its stocks to the CDC in 1978. In 1981 the last variola strains in the Netherlands were whisked to a plane transporting them to the CDC by a motorcycle-mounted escort. England sent its virus to Atlanta in 1982; South Africa, the last holdout, destroyed its remaining samples amid a flurry of publicity in 1983. Moscow now retains about 100 samples of the virus, the CDC about 400.

In Atlanta--and also, one assumes, in Mos-cow--the stocks are carefully tended, although the virus is now the subject of little or no research. At the CDC the samples are stored in stainless steel freezers under tight security. Officially they are the charges of Brian Mahy, director of the Division of Viral and Rickettsial Diseases. Over the years we’ve received stocks from countries where they’d accumulated, he says. The virus comes in a variety of forms. We’ve received tissue samples, cell cultures, even scabs from pustules. But we haven’t worked on most.

In fact, Dowdle adds, smallpox virus has hardly been cultured for the last ten years. Molecular biology has made it possible to clone chunks of the virus’s genetic material and work with these DNA copies, thus avoiding the danger of working with the live virus itself. On the relatively few occasions when the CDC has handled the virus at all--for example, to obtain DNA for cloning purposes--it has taken extraordinary precautions. Researchers work in spacesuits with their own air supply inside a sealed maximum security lab. Access is strictly controlled; exhaust air is carefully filtered; all waste products (including water used by researchers showering off after work) are sterilized. In short, the virus has long seemed much more trouble than it’s worth.

That’s what led the World Health Organization, the United States, and the USSR (as it was still known in December 1990) to agree jointly that the time was ripe for variola to suffer an appropriately ignominious death. Also, of course, there was the lingering fear that smallpox could still be used as a biological weapon--though it doesn’t make a very efficient one compared with other weapons such as the bacterium that causes anthrax or the virus responsible for Lassa fever. First of all, the mortality rate from smallpox is not that high, says Dowdle. And second, there’s enough vaccinia vaccine available to stop it from spreading.

Yet a handful of scientists were nonetheless reluctant to see variola eliminated when surveyed in a 1986 WHO poll. The risk of keeping the virus incarcerated, these scientists asserted, was negligible. One unnamed poll respondent even believed variola could still be circulating in nature among monkeys and humans, and therefore thought it pointless to kill off laboratory stocks.

But the main reason to save the variola species, they argued, is that the group it belongs to, the orthopoxviruses, have some unique characteristics. They’re the largest of all vi- ruses--the first virus ever glimpsed under a microscope was probably variola’s close relative, the cowpox virus, in 1887. The orthopoxviruses also sport intriguingly large double-stranded DNA genomes, among the longest known to exist in viruses. And they have the unusual ability to replicate in the cytoplasm of the cells they infect; they don’t need to get into the cells’ nucleus in order to take over their machinery and reproduce (even the AIDS retrovirus can’t do that). Given such peculiar traits, especially in these days of bioengineering, wouldn’t it make sense to preserve variola for future research?

Donald Hopkins, an epidemiologist at the Carter Center in Atlanta, thinks so. We humans simply can’t predict the future, he remarks. It is presumptuous and crazy, to say the least, for us to decide that we know all we need to know about this virus. How can we say that there never will be any potential use for it? If the virus is destroyed once and for all, and somebody theorizes a use for it, it could not be brought out and used again.

But this argument lost some of its force in the late 1980s, when it became feasible to map variola’s entire genome and sequence the order of its DNA building blocks, thus preserving a genetic blueprint of the virus for posterity. The CDC, WHO, and the Moscow Research Institute have agreed on a plan to sequence at least four variola strains before the 1993 deadline. These represent two highly virulent strains from Asia and Africa, says Dowdle, and two less virulent ones, from Africa and America. We may also sequence selected regions of the genome from other strains as well.

The tediously finicky work is being carried out simultaneously in Atlanta and Moscow, with an exchange of U.S. and Russian scientists. Because variola’s genome is large for a virus, some 175,000 building blocks long, researchers needed to make the job more manageable. So they cut its genetic material into segments by using a series of enzymes that snip DNA in different places. Then we reassembled these chunks, says Mahy. By figuring out where their ends overlap, we’ve laid out the whole genome in order. (As a simple analogy, imagine being handed three torn slips of paper, one saying is a bomb, a second there is, and a third, bomb in your desk. By matching the overlapping parts, you would soon get the message in the right order and head for the door.)

Now that variola’s genome is assembled in the correct order, the sequence of its individual building blocks is being worked out and written down so that it can be stored for all time in data bases. At that point not only the virus but any cloned chunks of its DNA can safely be destroyed, according to Giorgio Torrigiani. Should the need arise, researchers will have an accurate but harmless record of the virus: for example, if smallpox or a similar disease should ever reemerge, virologists will immediately be able to identify it by comparing its DNA with the preserved variola DNA sequences. Meanwhile, of course, vaccinia will still be around in abundance if mass immunizations should ever become necessary.

The World Health Organization, perhaps recalling the Birmingham tragedy, has also suggested some further precautions as the execution date nears. In 1985 six mysterious ampoules, dated 1952, turned up in London; nobody knew for sure what was in them, but variola was suspected and the vials were destroyed. As a result, WHO may ask all labs known to have experimented with the virus to make quite sure no overlooked vials remain tucked away in cobwebby corners or forgotten at the bottom of hoary freezers. At least one virologist has suggested that all freezers that once harbored variola should be emptied out and thoroughly disinfected, just in case virus escaped from a leaky vial: it can survive for many years at subzero temperatures.

But heat is another matter. In fact, incineration is the method planned for variola’s demise on a yet to be designated date in December 1993. So far at least, nobody has planned a ceremony. But the plan is to destroy both U.S. and Russian stocks on the appointed hour and day, with officials from both nations presiding over the executions.

The occasion doesn’t promise the grim pomp normally attendant on executions. Nothing very dramatic is going to happen, I imagine, Mahy says. We’ll simply put the entire contents of the freezer into a tin, put the tin into an autoclave [a laboratory oven], and turn on the heat. Forty-five minutes at a temperature of 266 degrees will do the job; the lights in nearby North Decatur will not even dim.

But a major human milestone will have been achieved. A plague and its cause will recede into history, and few will mourn their passing. You have to put it in psychological perspective, says Torrigiani. After all, we’re destroying an organism that has, over history, killed millions of human beings. Nobody’s going to miss it.